{"doi":"10.1074/jbc.ra120.014479","title":"The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis","abstract":"Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets. Poly(ADP-ribose) polymerase 1 (PARP1), in the presence of NAD+, catalyzes poly(ADP-ribosyl)ation, generating poly(ADP-ribose) (PAR) chains attached to acceptor proteins (1Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1113) Google Scholar, 2Gupte R. Liu Z. Kraus W.L. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev. 2017; 31: 101-126Crossref PubMed Scopus (261)","journal":"Journal of Biological Chemistry","year":2020,"id":49718,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":236,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":243766,"name":"Mayu Onishi","orcid":null,"position":1,"is_corresponding":false},{"id":243767,"name":"Arina Uno","orcid":null,"position":2,"is_corresponding":false},{"id":243768,"name":"Akari Tanimichi","orcid":null,"position":3,"is_corresponding":false},{"id":243769,"name":"Akari Nobeyama","orcid":null,"position":4,"is_corresponding":false},{"id":243770,"name":"Mana Mori","orcid":null,"position":5,"is_corresponding":false},{"id":243771,"name":"Sayaka Yamada","orcid":null,"position":6,"is_corresponding":false},{"id":241246,"name":"Shigeru Negi","orcid":"0000-0002-3526-4140","position":7,"is_corresponding":false},{"id":241247,"name":"Xiangning Bu","orcid":"0000-0001-6291-7656","position":8,"is_corresponding":false},{"id":241248,"name":"Jiro Kato","orcid":"0000-0003-0318-1794","position":9,"is_corresponding":false},{"id":241249,"name":"Joel Moss","orcid":"0000-0003-1788-1927","position":10,"is_corresponding":false},{"id":243772,"name":"Noriko Sanada","orcid":null,"position":11,"is_corresponding":false},{"id":241250,"name":"Ryoichi Kizu","orcid":"0000-0002-2673-9108","position":12,"is_corresponding":false},{"id":241251,"name":"Takeshi Fujii","orcid":"0000-0002-0217-4050","position":13,"is_corresponding":false},{"id":241245,"name":"Masato Mashimo","orcid":"0000-0003-3922-7344","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T20:37:28.027635Z","pmid":"33168626","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}